Novel Genes of the Male Reproductive System: Potential Roles in Male Reproduction and as Non-hormonal Male Contraceptive Targets.

The development of novel non-hormonal male contraceptives represents a pivotal frontier in reproductive health, driven by the need for safe, effective, and reversible contraceptive methods. This comprehensive review explores the genetic underpinnings of male fertility, emphasizing the crucial roles of specific genes and structural variants (SVs) identified through advanced sequencing technologies such as long-read sequencing (LRS). LRS has revolutionized the detection of structural variants and complex genomic regions, offering unprecedented precision and resolution over traditional next-generation sequencing (NGS). Key genetic targets, including those implicated in spermatogenesis and sperm motility, are highlighted, showcasing their potential as non-hormonal contraceptive targets. The review delves into the systematic identification and validation of male reproductive tract-specific genes, utilizing advanced transcriptomics and genomics studies with validation using novel knockout mouse models. We discuss the innovative application of small molecule inhibitors, developed through platforms like DNA-encoded chemistry technology (DEC-Tec), which have shown significant promise in preclinical models. Notable examples include inhibitors targeting serine/threonine kinase 33 (STK33), soluble adenylyl cyclase (sAC), cyclin-dependent kinase 2 (CDK2), and bromodomain testis associated (BRDT), each demonstrating nanomolar affinity and potential for reversible and specific inhibition of male fertility. This review also honors the contributions of Dr. David L. Garbers whose foundational work has paved the way for these advancements. The integration of genomic, proteomic, and chemical biology approaches, supported by interdisciplinary collaboration, is poised to transform male contraceptive development. Future perspectives emphasize the need for continued innovation and rigorous testing to bring these novel contraceptives from the laboratory to clinical application, promising a new era of male reproductive health management.

A comparative study of hormonal contraceptive use and vitamin D levels at Gondar Town 2023.

Vitamin D deficiency is an emerging public health problem globally, with devastating health consequences. Some studies suggest that exogenous sex hormones, found in hormonal contraceptives, may enhance vitamin D levels. However, the reasons for this association are not fully understood, as women using hormonal contraception may have different lifestyle habits affecting their vitamin D status. Therefore, this study seeks to explore the relationship between hormonal contraceptive use and vitamin D levels. A Facility based comparative cross-sectional study was conducted in Gondar town from February to April 2023, involving a total of 162 women using three types of hormonal contraceptives (Norplant, DMPA, and COC) and 162 age and BMI-matched non-users as controls in a 1:1 ratio. Participants were selected using systematic random sampling. A semi-structured questionnaire was used to collected data regarding the socio-demographic, economic, obstetric, lifestyle, and clinical information. 5 milliliters of blood samples were collected from each participant for Laboratory analysis of serum vitamin D, calcium, and alkaline phosphates using a Beckman Coulter chemistry analyzer. Independent t-tests, ANOVA with post hoc Bonferroni test was used to compare statistics between the two groups, and logistic regression models to identify factors associated with Vitamin D deficiency. The mean serum Vitamin D levels of Norplant, DMPA, and COC users were 24.08 (± 5.17), 24.83 (± 5.52), and 31.90 (± 6.94) respectively; whereas control group has mean Vitamin D level of 22.00 (± 7.97). On the current study the prevalence of Vitamin D deficiency (< 20 ng/ml) among hormonal contraceptive users was found to be 21.6% (35/162), whereas 48.14% (78/162) of non-user controls had vitamin D deficiency. The odds of having Vitamin D deficiency was higher among participants who attained higher education, who never eat fish and have never been used vitamin D Supplements. However, the use of combined oral contraceptives (COC) shown to reduce the odd of having vitamin D deficiency by 90%. Similarly, individuals with normal and hypercalcemia state shown to have lower odd of having Vitamin D deficiency. Users of combined oral contraceptives (COC) had significantly higher mean serum Vitamin D levels compared to users of Norplant and DMPA, as well as non-users. The prevalence of Vitamin D deficiency was lower among COC users compared to non-users, highlighting a potential protective effect of COC use against Vitamin D deficiency.

The Impact of Hormonal Contraceptives on the Incidence and Progression of Cardiovascular Diseases in Women: A Systematic Review.

This systematic review examines the impact of hormonal contraceptives on the incidence and progression of cardiovascular diseases in women. We analyzed 14 high-quality studies published between 1998 and 2018, including meta-analyses, cohort studies, case-control studies, and systematic reviews. The aim was to synthesize the current understanding of the relationship between various hormonal contraceptives and cardiovascular risks, focusing on outcomes such as venous thromboembolism, ischemic stroke, and myocardial infarction. The 14 selected studies represent a comprehensive and diverse body of evidence, allowing for a nuanced analysis of the topic. Our findings indicate that combined oral contraceptives are associated with an increased risk of cardiovascular events, with the magnitude of risk varying based on estrogen dose, progestogen type, and individual risk factors. The review of these studies highlights the importance of personalized risk assessment in contraceptive counseling and prescribing practices. By synthesizing data from these key studies, we provide a consolidated view of the current state of knowledge regarding hormonal contraceptives and cardiovascular health, offering valuable insights for both clinicians and researchers in the field.

Self-Reported Menstrual Health, Symptomatology, and Perceived Effects of the Menstrual Cycle for Elite Junior and Senior Football Players.

PURPOSE: To describe the self-reported menstrual health, symptomatology, and perceived effects of the menstrual cycle on athletic performance for national and international Australian football (soccer) players. METHODS: Players from national and domestic teams were invited to complete an online questionnaire regarding menstrual health, use of hormonal contraceptives (HCs), negative symptomatology, and perceived disruption of the menstrual cycle to performance. Descriptive statistics and binomial regressions with odds ratios (OR) were used to report the relationship of menstrual-related variables with perceived performance disruption. RESULTS: A total of 199 players (20.9 [5.1] y) completed the questionnaire, with 18% of players reporting using HCs. One primary amenorrhea case was detected, and 26% of players reported menarche at age ≥15 years. For non-HC users, the prevalence of secondary amenorrhea was 2%, oligomenorrhea was 19%, and heavy menstrual bleeding was 11%. Ninety-seven percent of players reported experiencing physical or affective menstrual symptoms (5 [1.3] per player), and 40% of all players reported that menstrual symptoms impacted their ability to work, study, train, or compete. Furthermore, 40% of players perceived their training or performance to be disrupted by the menstrual cycle. Increasing number of menstrual symptoms (OR = 1.43; 95% CI, 1.28-1.62; P < .001), heavy menstrual bleeding (OR = 12.73; 95% CI, 3.4-82.8; P < .001), and pelvic pain (OR = 3.40; 95% CI, 1.7-7.2; P < .001) increased the likelihood of perceiving the menstrual cycle to disrupt performance. CONCLUSION: Heavy menstrual bleeding and HC use were low among this cohort of national and international footballers, whereas amenorrhea and oligomenorrhoea were comparable with other football populations. Nearly all players reported menstrual symptoms, and increased symptomatology was associated with greater perceived effects on performance.

Association Between Intrauterine System Hormone Dosage and Depression Risk.

OBJECTIVE: The authors compared the associated risk of incident depression between first-time users of low-, medium-, and high-dose levonorgestrel-releasing intrauterine systems (LNG-IUSs). METHODS: This national cohort study was based on Danish register data on first-time users of LNG-IUSs, 15-44 years of age, between 2000 and 2022. Cox regression and a G-formula estimator were used to report 1-year average absolute risks, risk differences, and risk ratios of incident depression, defined as initiation of an antidepressant or receipt of a depression diagnosis, standardized for calendar year, age, education level, parental history of mental disorders, endometriosis, menorrhagia, polycystic ovary syndrome, dysmenorrhea, leiomyoma, and postpartum initiation. RESULTS: In total, 149,200 women started using an LNG-IUS, among whom 22,029 started a low-dose one (mean age, 22.9 years [SD=4.5]), 47,712 a medium-dose one (mean age, 25.2 years [SD=6.2]), and 79,459 a high-dose one (mean age, 30.2 years [SD=5.6]). The associated subsequent 1-year adjusted absolute risks of incident depression were 1.21% (95% CI=1.06-1.36), 1.46% (95% CI=1.33-1.59), and 1.84% (95% CI=1.72-1.96), respectively. For the users of high-dose LNG-IUSs, the risk ratios were 1.52 (95% CI=1.30-1.74) and 1.26 (95% CI=1.10-1.41) compared with users of the low- and medium-dose LNG-IUSs, respectively. For users of medium-dose LNG-IUSs, the risk ratio was 1.21 (95% CI=1.03-1.39) compared with users of low-dose LNG-IUSs. CONCLUSIONS: First-time use of an LNG-IUS was positively associated with incident depression in an LNG-dose-dependent manner across low-, medium-, and high-dose LNG-IUSs. Although the observational design of the study does not permit causal inference, the dose-response relationship contributes to the body of evidence suggesting a relationship between levonorgestrel exposure and risk of depression.

The male birth control pill - A new approach to family planning and population control.

With the increase in the world's population, contraception is crucial in population control strategies. Majority of contraceptives produced today are targeted at women; many of whom experience side effects, leading to the discontinuation of these contraceptives after a year of use. As the use of condoms and vasectomies has been subjected to scrutiny, it is necessary for the development of male birth control (BC). Attempts to achieve this include hormonal and non-hormonal contraception. Hormonal contraception prevents the production of the sperm in the testes; but this mode of BC has been found to be ineffective while also causing behavioural changes in men. In contrast, non-hormonal male contraception focuses on rendering the sperm immotile to prevent fertilization post-copulation. Soluble adenylate cyclase is an area of research that has shown promise in this field. Furthermore, two inhibitors, TDI-10299 and TDI-11861, have been developed and tested, with the latter, showing greater potency and longer activity, in mice models. Overall, by developing non-hormonal male contraceptives, men will have more control over their reproductive health. Nonetheless, before such contraceptives can be made widely available, it is important that further research takes place to ensure the safety and effectiveness of these methods.

Assessing the impact of hormonal contraceptive use on menstrual health among women of reproductive age - a systematic review.

BACKGROUND: Contraceptive methods are well-established in their ability to prevent pregnancy and increase individual agency in childbearing. Evidence suggests that contraceptives can also be used to treat adverse conditions associated with menstruation, including abnormal and prolonged uterine bleeding, heavy menstrual bleeding, painful menstruation, endometriosis, uterine fibroids, and premenstrual dysphoric disorders.This review investigates the effects of contraceptive techniques such as contraceptive pills, and long-acting reversible contraceptives (e.g. intrauterine devices, implants) on menstrual morbidity. METHODS: Over ten databases with no geographical boundaries were searched from inception until October 2023. Study designs were one of the following types to be included: parallel or cluster randomised controlled trials, controlled clinical trials, controlled before and after studies, interrupted time series studies, cohort or longitudinal analyses, regression discontinuity designs, and case-control studies. Ten team members screened the papers in pairs with a Kappa score of more than 7, and Covidence was used. Conflicts were resolved by discussion, and the full papers were divided among the reviewers to extract the data from eligible studies. RESULTS: Hormonal contraceptives are considered a well-tolerated, non-invasive, and clinically effective treatment for abnormal and prolonged uterine bleeding, heavy menstrual bleeding, painful menstruation, endometriosis, uterine fibroids, and premenstrual dysphoric disorders. Our studies investigating quality of life or well-being in women with heavy menstrual bleeding, endometriosis, or uterine fibroids have found improvements in all dimensions assessed. CONCLUSIONS: Hormonal contraceptives significantly reduce pain, symptom severity, and abnormal bleeding patterns associated with women who suffer from heavy menstrual bleeding, endometriosis, and uterine fibroids.

Hormonal contraceptives significantly reduce pain, symptom severity, and abnormal bleeding patterns associated with women who suffer from heavy menstrual bleeding, endometriosis, and uterine fibroids. Findings can inform clinical practice and policy decisions to ensure that women have access to safe and effective contraceptive options that promote both reproductive and non-reproductive health.

Auditing the representation of hormonal contraceptives in studies assessing exercise performance in women.

Hormonal contraceptive (HC) users have a different ovarian hormonal profile compared to eumenorrheic women. Due to the prevalence of HC use amongst sportswomen, there has been increased research efforts to understand their impact on exercise performance. The aim was to audit this research. Studies identified were assessed for HC type, athlete calibre, performance outcome, study design, and quality of methodological control regarding ovarian hormonal profiles. Sixty-eight different HCs were reported across 61 studies. Monophasic combined oral contraceptive (OCP) pills represented 60% of HCs, followed by other pills [34%, phasic-combined, progestogen-only, and un-specified], phasic and long acting reversible contraceptives [5%, vaginal ring, patch, implant, injection, intrauterine system] and unspecified HCs (1%). Eleven percent of participants using HCs were classified as highly trained or elite/international with no participants being classed as world class. Whilst the number of studies involving HCs has increased two-fold over the past decade, the number of studies ranked as gold standard has not increased (HC; 2003-57%, 2011-55%, 2022-43%. OCP; 2003-14%, 2011-17%, 2022-12%). Future research assessing HCs and exercise performance should adopt high-quality research designs and include a broader range of HCs in highly trained to world-class populations to increase the reach and impact of research in this area.

Counseling Women About Sexual Health Effects of Contraceptives.

Background: Choosing a contraceptive method is a pivotal decision for patients, whereas health care professionals (HCPs) face challenges in providing suitable recommendations. Adverse sexual effects often lead to dissatisfaction and discontinuation of contraceptives, underscoring the importance of thorough counseling and shared decision making between HCPs and patients. Objective: This article aims to investigate the relationship between contraceptive methods and female sexual function through a comprehensive review of available literature, emphasizing the importance of considering sexual health in contraceptive prescription and management. Methods: A systematic analysis of existing literature, incorporating studies utilizing validated sexual health questionnaires, was conducted to elucidate the intricate interplay between contraceptives and female sexual function. Results: The review encompasses various contraceptive methods, including combined hormonal contraceptives, progestin-only pills, depot medroxyprogesterone acetate, subdermal contraceptive implants, hormonal intrauterine devices, permanent sterilization, and barrier methods. Insights gleaned from the analysis shed light on the impact of these methods on female sexual health. Conclusion: Comprehensive understanding of the effects of contraceptives on female sexual function is crucial for both HCPs and patients. By integrating sexual health considerations into contraceptive surveillance, compliance can be improved, contraceptive efficacy optimized, and the risk of unwanted pregnancies minimized. This review underscores the significance of tailored counseling and shared decision making in contraceptive management, particularly for cisgender women.

Prevalence of Depression Among Women Using Hormonal Contraceptives in Mogadishu, Somalia: A Cross-Sectional Study.

Background: Depression is a global health concern with significant consequences, especially for women. Hormonal changes and gender disparities contribute to its prevalence. Hormonal contraceptives are widely used among women of reproductive age, but some users report mood-related side effects. Purpose: This study aims to investigate the relationship between hormonal contraceptive use and depression among women in Mogadishu, Somalia. Methods: An analytical cross-sectional study was conducted at two hospitals in Mogadishu, targeting married women aged 15-49 using hormonal contraceptives. A sample size of 227 participants was determined, and data was collected using semi-structured questionnaires, including the Patient Health Questionnaire-9 (PHQ-9) to assess depression. The data were analyzed using SPSS version 25, including multivariate logistic regression. Results: The prevalence of depression among participants was 33.5%, with significant associations observed between depression and occupation, income level, type of hormonal contraceptive used, and duration of contraceptive use. Housewives, individuals with lower income, users of oral pills and implant methods, as well as those with shorter durations of contraceptive use, constituted the high-risk groups for depression. Conclusion: Depression poses a concern among women using hormonal contraceptives in Mogadishu, Somalia. Healthcare providers should educate women about potential side effects and consider individualized contraceptive recommendations. Mental health support initiatives and awareness campaigns should be introduced. Future research is recommended to further understand and address depression in this context.

Relationship between classic indicators of health behaviour and contraceptive choices in women in Flanders.

BACKGROUND: In this study we shed light on ongoing trends in contraceptive use in Flanders (Belgium). Building on the fundamental cause theory and social diffusion of innovation theory, we examine socio-economic gradients in contraceptive use and the relationship to health behaviours. METHODS: Using the unique and recently collected (2020) ISALA data, we used multinomial logistic regression to model the uptake of contraceptives and its association to educational level and health behaviour (N:4316 women). RESULTS: Higher educated women, and women with a healthy lifestyle especially, tend to use non-hormonal contraceptives or perceived lower-dosage hormonal contraceptives that are still trustworthy from a medical point of view. Moreover, we identified a potentially vulnerable group in terms of health as our results indicate that women who do not engage in preventive health behaviours are more likely to use no, or no modern, contraceptive method. DISCUSSION: The fact that higher educated women and women with a healthy lifestyle are less likely to use hormonal contraceptive methods is in line with patient empowerment, as women no longer necessarily follow recommendations by healthcare professionals, and there is a growing demand for naturalness in Western societies. CONCLUSION: The results of this study can therefore be used to inform policy makers and reproductive healthcare professionals, since up-to-date understanding of women's contraceptive choices is clearly needed in order to develop effective strategies to prevent sexually transmitted infections and unplanned pregnancies, and in which women can take control over their sexuality and fertility in a comfortable and pleasurable way.

Progesterone-Only Contraceptive-Induced Ischemic Colitis.

Ischemic colitis (IC) occurs when there is a temporary lack of adequate blood supply to the intestines, particularly in vulnerable areas such as the splenic flexure and sigmoid colon, which lack sufficient collateral blood vessels. Although primarily seen in older individuals with atherosclerotic risk factors, IC can also be triggered by hormonal contraceptives in young women. Although estrogen-containing oral contraceptives are known to increase thromboembolic risk, the impact of progesterone is not well understood. We report a unique case of biopsy-confirmed IC in a previously healthy 30-year-old woman who presented with abdominal pain and bloody diarrhea 2 months after initiation of progesterone-only oral contraceptive. This occurrence, although rare, underscores the need for further research on the impact of progesterone on coagulation, especially concerning mesenteric arteries.

Correlation of sexual desire with sexual hormone binding globulin and free androgen index in women using combined contraceptives.

PURPOSE: To correlate the sexual desire levels with sexual hormone binding globulin and free androgen index in women taking different types of hormonal contraceptives (HCs) containing ethinylestradiol (EE), oestradiol valerate (E2V), 17ß-oestradiol (E2), or estetrol (E4), combined or in phasic formulation with different progestogens having antiandrogenic properties. METHODS: Three hundred and sixty-seven women (age range 18-46) participated in the study. SHBG and total testosterone (TT) were measured, and the Free Androgen Index (FAI) was calculated. The Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale (FSDS) questionnaires were used to assess sexual function and distress, respectively. RESULTS: The highest SHBG values and the lowest FAIs were obtained of women on HCs containing EE than those of women on HCs containing E2V/17ß E2 or E4 (p < 0.001). Desire scores and FSFI total scores were lower in women on HCs with EE than in those using HCs containing E2V, 17ß E2, or E4 (p ≤ 0.001). The women who were on HCs containing EE reported FSDS levels higher than those containing all the other types of oestrogen. Finally, sexual desire and FSFI total scores had a negative correlation with the SHBG values and a positive correlation with FAI percentage (p ≤ 0.0001). CONCLUSIONS: A minority of women using HCs with EE might experience a decreased sexual desire. This was not observed in women on HCs containing E2V, 17 E2, or E4. To avoid HC discontinuation, due to sexual desire reduction, HCs having minor antiandrogenic effects could be taken into consideration.

Experts' view on the role of oestrogens in combined oral contraceptives: emphasis on oestetrol (E4).

Introduction: The evolution of contraception has been crucial for public health and reproductive well-being. Over the past 60 years, combined oral contraceptives (COCs) have remained an important part of the contraceptive landscape worldwide; continued development has worked toward maintaining efficacy and improving safety. Methods: Seven global experts convened to discuss the clinical relevance of the oestrogen in COCs, focusing on the impact of the new oestrogen, oestetrol (E4). Participants then commented through an online forum on the summary content and other participants' feedback. We prepared this report to describe the experts' views, their follow-up from the open forum and the evidence supporting their views. Results: Ethinylestradiol (EE) and oestradiol (E2) affect receptors similarly whereas E4 has differential effects, especially in the liver and breast. Adequate oestrogen doses in COCs ensure regular bleeding and user acceptability. EE and E4 have longer half-lives than E2; accordingly, COCs with EE and E4 offer more predictable bleeding than those with E2. Oestrogen type and progestin influence VTE risk; E2 poses a lower risk than EE; although promising, E4/DRSP VTE risk is lacking population-based data. COCs alleviate menstrual symptoms, impact mental health, cognition, libido, skin, and bone health. Conclusion: Oestrogens play an important role in the contraceptive efficacy, bleeding patterns, and overall tolerability/safety of COCs. Recent studies exploring E4 combined with DRSP show promising results compared to traditional formulations, but more definitive conclusions await further research.

Menstrual cycle phases and dosage of synthetic hormonal contraceptives influence diurnal rhythm characteristics of distal skin temperature.

This study aimed to explore how natural menstrual cycle phases and dosage of oral hormonal contraceptives (OC) influence the diurnal rhythm of distal skin temperature (DST) under real-life conditions. Participants were 41 healthy females (23.9 ± 2.48 y), comprising 27 females taking monophasic hormonal oral contraceptives (OC users) and 14 females with menstrual cycles (non-OC users). Wrist DST was continuously recorded and averaged over two consecutive 24-hour days during (pseudo)follicular and (pseudo)luteal menstrual phases. Diurnal rhythm characteristics, i.e. acrophase and amplitude, describing timing and strength of the DST rhythm, respectively, were calculated using cosinor analysis. Results show that non-OC users experienced earlier diurnal DST maximum (acrophase, p = 0.019) and larger amplitude (p = 0.016) during the luteal phase than during the follicular phase. This was observed in most (71.4%) but not all individuals. The OC users showed no differences in acrophase or amplitude between pseudoluteal and pseudofollicular phases. OC users taking a higher dosage of progestin displayed a larger amplitude for DST rhythm during the pseudoluteal phase (p = 0.009), while estrogen dosage had no effect. In conclusion, monophasic OC cause changes in diurnal DST rhythm, similar to those observed in the luteal phase of females with menstrual cycles, suggesting that synthetic progestins act in a similar manner on skin thermoregulation as progesterone does.

Oral manifestations in women using hormonal contraceptive methods: a systematic review.

OBJECTIVES: To investigate the oral manifestations in women of reproductive age using hormonal contraceptive methods. MATERIALS AND METHODS: This review is based on the PRISMA statement. A literature search incorporated observational studies from the last 21 years. An investigative question was formulated using the PICO model, studies were selected, and a quality analysis was performed using the modified STROBE guidelines. A bibliometric analysis was performed, and the data were examined. RESULTS: Thirteen articles were included, with the majority evaluating periodontal status. Others analyzed factors such as the presence of alveolar osteitis, oral candidiasis, and salivary microbiome dysbiosis. Ten articles were deemed to have a low risk of bias. CONCLUSIONS: Hormonal contraceptives may increase the risk of alveolar osteitis following tooth extraction and increase the presence of the Candida species in the oral cavity. They also affect the periodontium, such as the frequent development of gingivitis, but do not lead to changes in the salivary microbiome. CLINICAL RELEVANCE: The increasing number of women using hormonal contraceptives and the knowledge that these contraceptives can produce oral cavity alterations underscore the need to evaluate the oral manifestations found in these women.

Exploring the relationship between contraceptive medication use and concussion recovery in female collegiate athletes: a LIMBIC MATARS consortium investigation.

OBJECTIVE: While recovery from concussion is variable, women are more likely to report symptoms, experience worse outcomes, and have longer recovery trajectories following concussion than men. Preliminary data suggest that hormonal fluctuations, specifically progesterone, may be associated with this variability. This study aimed to understand the effect of contraceptive medication on concussion recovery. METHODS: A retrospective chart review using consensus-based common data elements was conducted at 11 NCAA institutions as part of the LIMBIC MATARS consortium. Participants included female collegiate athletes diagnosed with a concussion who did (n = 117) or did not report (n = 339) contraceptive medication use. Number of days between diagnosis and symptom resolution were compared using Mann-Whitney U tests. Self-reported diagnosis of attention deficit hyperactivity disorder, concussion history, anxiety, and depression was compared using Chi-squared tests. RESULTS: The proportions of participants who did or did not take contraceptive medication were similar across covariates. Female athletes regardless of contraceptive medication use recovered similarly following a concussion. CONCLUSIONS: Our findings suggest that contraceptive medication use did not significantly impact concussion recovery. Future prospective investigations should examine documentation practices and operationalize terminology for hormonal contraceptive medication to better understand their role on recovery from sport-related concussion in female collegiate athletes.

Hormonal intrauterine devices and heat exchange during exercise.

Synthetic progestins in oral contraceptives are thought to blunt heat dissipation by reducing skin blood flow and sweating. However, whether progestin-releasing intrauterine devices (IUDs) modulate heat loss during exercise-heat stress is unknown. We used direct calorimetry to measure whole-body total (dry + evaporative) heat loss in young, physically active women (mean (SD); aged 24 (4) years, V ̇ O 2 peak ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{peak}}}}$ 39.3 (5.3) ml/kg/min) with (IUD; n = 19) and without (Control; n = 17) IUDs in the follicular and luteal phases of the menstrual cycle during light- and moderate-intensity exercise at fixed rates of heat production (∼175 and ∼275 W/m2 ) in 30°C, ∼21% relative humidity. Between-group and -phase differences were evaluated using traditional hypothesis testing and statistical equivalence testing within pre-determined bounds (±11 W/m2 ; difference required to elicit a ±0.3°C difference in core temperature over 1 h) in each exercise bout. Whole-body total heat loss was statistically equivalent between groups within ±11 W m-2 (IUD-Control [90% CIs]; Light: -2 [-8, 5] W/m2 , P = 0.007; Moderate: 0 [-6, 6] W/m2 , P = 0.002), as were dry and evaporative heat loss (P ≤ 0.023), except for evaporative heat loss during moderate-intensity exercise (equivalence: P = 0.063, difference: P = 0.647). Whole-body total and evaporative heat loss were not different between phases (P ≥ 0.267), but dry heat loss was 3 [95% CIs: 1, 5] W/m2 greater in the luteal phase (P ≤ 0.022). Despite this, all whole-body heat loss outcomes were equivalent between phases (P ≤ 0.003). These findings expand our understanding of the factors that modulate heat exchange in women and provide valuable mechanistic insight of the role of endogenous and exogenous female sex hormones in thermoregulation. KEY POINTS: Progestin released by hormonal intrauterine devices (IUDs) may negatively impact heat dissipation during exercise by blunting skin blood flow and sweating. However, the influence of IUDs on thermoregulation has not previously been assessed. We used direct calorimetry to show that IUD users and non-users display statistically equivalent whole-body dry and evaporative heat loss, body heat storage and oesophageal temperature during moderate- and high-intensity exercise in a warm, dry environment, indicating that IUDs do not appear to compromise exercise thermoregulation. However, within IUD users and non-users, dry heat loss was increased and body heat storage and oesophageal temperature were reduced in the luteal compared to the follicular phase of the menstrual cycle, though these effects were small and unlikely to be practically meaningful. Together, these findings expand our understanding of the factors that modulate heat exchange in women and have important practical implications for the design of future studies of exercise thermoregulation.

Repeated exposure to physiologically effective doses of contraceptive hormones ethinyl estradiol or levonorgestrel do not alter the reinforcing effects of a brief visual stimulus in ovary-intact rats.

Estradiol and progesterone potentiate and attenuate reward processes, respectively. Despite these well-characterized effects, there is minimal research on the effects of synthetic estrogens (e.g., ethinyl estradiol, or EE) and progestins (e.g., levonorgestrel, or LEVO) contained in clinically-utilized hormonal contraceptives. The present study characterized the separate effects of repeated exposure to EE or LEVO on responding maintained by a reinforcing visual stimulus. Forty ovary-intact female Sprague-Dawley rats received either sesame oil vehicle (n = 16), 0.18 µg/day EE (n = 16), or 0.6 µg/day LEVO (n = 8) subcutaneous injections 30-min before daily one-hour sessions. Rats' responding was maintained by a 30-sec visual stimulus on a Variable Ratio-3 schedule of reinforcement. The day after rats' last session, we determined rats estrous cycle phase via vaginal cytology before sacrifice and subsequently weighing each rat's uterus to further verify the contraceptive hormone manipulation. The visual stimulus functioned as a reinforcer, but neither EE nor LEVO enhanced visual stimulus maintained responding. Estrous cytology was consistent with normal cycling in vehicle rats and halting of normal cycling in EE and LEVO rats. EE increased uterine weights consistent with typical uterotrophic effects observed with estrogens, further confirming the physiological impacts of our EE and LEVO doses. In conclusion, a physiologically effective dose of neither EE nor LEVO did not alter the reinforcing efficacy of a visual stimulus reinforcer. Future research should characterize the effects of hormonal contraceptives on responding maintained by other reinforcer types to determine the generality of the present findings.